Since the elucidation of the clinical significance of certain naturally-occurring peptides and the development of various techniques for their synthesis, it has become clear that these substances will be clinically practical only if a convenient method for delivering them in controlled doses can be provided. Because peptides are destroyed in the digestive tract when taken orally, they must be administered parenterally. Furthermore, therapies involving bioactive peptides often demand injections at regular intervals for extended periods of time. In view of these limitations, certain controlled release drug delivery systems for providing continuous parenteral dosing of peptides have been sought. While continuous infusion systems such as pumps have been used, they are cumbersome, expensive and not completely practical.
Efforts have been made to employ existing drug delivery systems based on biodegradable polymers as subcutaneous implants for the controlled release of peptides. Current polymer-based systems are typically combined with a drug in one of the following ways: (1) Diffusion systems in which a reservoir of drug is contained in a polymer capsule and drug delivery is by the slow diffusion of the drug through the interstices of the polymer capsule wall; (2) matrix erosional systems (monolithic systems) in which a drug is evenly distributed in a polymer matrix and is released as the polymer breaks down in biological fluid; and (3) diffusion/erosion systems in which drug release occurs as a result of diffusion of the drug through the polymer matrix and release of the drug as the surface of the device continually erodes.
Numerous difficulties associated with achieving the release of peptides from polymer systems have been encountered in the laboratory. While these difficulties are acknowledged, they are not well understood and may be the result of several physiochemical events acting in concert. For example, certain peptides tend to aggregate--perhaps due to ionization--under conditions where high concentrations of the peptides come into contact with phosphate buffered physiologic saline solution used to simulate the extracellular environment the implant will be in. This effect has proven to be a significant obstacle in the development of diffusion type polymer devices. So-called aggregation is particularly likely in the case of selectively porous polymer capsules. These capsules present a synthetic diffusion layer having pores of specific size and frequency whereby biological fluids first seep into the capsule, dissolve the encapsulated drug and then carry the drug back out to a saturated reservoir (formed by the normal reaction of subcutaneous fibrous tissue to the presence of the capsule) surrounding the implant. In such systems, depending on the net charge of the molecule and the size of the pores (dictated by the size of the molecule), enough biological fluid will enter the capsule to reach a critical point at which aggregation takes place and the drug assumes the consistency of a thick gel that resists diffusion from the capsule.
Alternatively, there are those diffusional capsules which rely on the seeping out of drug through the interstices of the polymer structure. With the exception of a few peptides of comparatively low molecular weights (such as luteinizing hormone-releasing hormone), peptide molecules of physiologic interest have been shown to be too large to escape these capsules.
Difficulties with polymer-based delivery systems also may arise from a reaction between the peptide and the hydrolized by product of the polymer or some additive used as a wetting agent, or a confluence of such circumstances. Conversely, the known monolithic polymer systems exhibit a bulk erosion, thus releasing too much (or all) of the drug and cannot be relied upon to provide appropriate release kinetics over long periods of time.
Nonpolymer-based devices have also been used as subcutaneous implants for delivering a drug. Initially, pellets formed by compressing mixtures of a drug and an excipient were attempted. Such pellets, however, tended to disintegrate after a short time and thus exhibited an undesirable burst effect of the active ingredient and short duration of action. Later, pellets formed by "fusing", rather than compressing, mixtures of a drug and an excipient were attempted. In particular, fused pellets for the controlled release of steroid hormones were made by melting a mixture of cholesterol and a steroidal hormone under strictly controlled conditions. The completely melted ixture would be allowed to cool and recrystallize. It has been determined that such a fused pellet, if properly manufactured, releases steroidal hormones in a relatively even and continuous manner over a period of a year or more. It is believed that diffusion is minimized in such pellets, if existent at all. Rather, the uniform release rate is due to the slow surface erosion of the pellet, the active ingredient being evenly distributed across the surface of the pellet and uniformly throughout its volume.
Fused implants have never been used as a system for delivering peptides. In the totally-fused pellet, the hard, final matrix is arrived at by the creation of a complete melt that recrystallizes during cooling. This is not possible with a peptide molecule which, if melted, may fragment and lose its bioactivity.
The present invention provides a simple, inexpensive, nonpolymer, erodible pellet for subcutaneous implantation providing continuous parenteral release of peptides. The present invention also provides a method and apparatus for the preparation of such bioerodible pellets.